Process of and compositions for combating epileptic seizures with atrolactamide



United States Patent '0 PROCESS OF ANDCOMPOSITIONS FOR COMBAT- EglLEPTICSEIZURES WITH ATROLAC- No Drawing. Application September 6, 1952, SerialNo. 308,299

Claims. (Cl. 167-65) This invention relates to therapeutic compositionsand processes, and more particularly to compositions and rocesses forcontrolling epileptic seizures.

Briefly, this invention is directed to a composition for o'ntrollingepileptic seizures, comprising atrolactamide nd a pharmaceuticalcarrier. The present invention also is directed to a process forcontrolling epileptic seizures which'comprises administering to a humanbeing a daily dosage of not more than approximately 16 grams ofatrolactarnide.

Among the several objects of this invention may be noted the provisionof new and effective compositions and processes for controllingepileptic seizures; the provision of compositions which are particularlyeifective against grand mal, psychomotor, Jacksonian and petit malvariant epileptic seizures, either when occurring alone or whenassociated with any other form of epilepsy; the provision ofcompositionsof the class described which produce few side reactions; and theprovision of such compositions which do not accentuate one type ofseizure where it occurs together with other types. Other objects andfeatures will be in part apparent and in part pointed out hereinafter.

The invention accordingly comprises the products and methods hereinafterdescribed, the scope of the invention being indicated in the followingclaims.

There are in this country between 800,000 and 1,500,-

;000 epileptics, according to figures obtained from the American LeagueAgainst Epilepsy. Dr. Frederic A. Gibbs stated there are over a millionpersons with epilepsy in the United States, for epilepsy is as common asdiabetes (The Journal of the Michigan State Medical Society,vol. 50, pp.145-148, 167; February 1951).

I Epilepsy is defined as a paroxysmal cerebral dysrhythmia (Gibbs, F.,Gibbs, E., and Lennox, 1937); it is based on a disturbance of nerve cellmetabolism which results in a disorder ofthe energy economy ofcerebralneurones,

garded as partial epilepsies in which the spatial and temporalregulation of energy release is sufficiently disorganized to produceclinical symptoms, but not so completely disorganized that the localsigns and evidences of limited disorganization are lost. Such seizuresare submaximal; they include petit mal, petit mal variant, psychomotor,focal, Jacksonian, myoclonic, thalamic and hypothalamic seizures.

, Generalizedconvulsions (grand mal epilepsy) are regarded asmanifestations of maximal (or near maximal) cerebral dysrhythmias and asevidence that a seizure discharge has spread so far and become sointense that the local signs and special features of its origin arelost. This is the most dramatic of all epileptic seizures and, in fact,is the one which is commonly regarded as an epileptic seizure. It isassociated with an excessive release which in many instances force "iceof energy per unit time from the cerebral neurones. Clinically thepatient becomes rigid for a matter of seconds or up to a minute. This isfollowed by generalized jerking movements which last a variable lengthof time and terminate in a stupor. During an attack a patient may bitehis tongue or be incontinent of urine or feces. Some victims have manyattacks a day while others may have only one or two attacks per year.About 8% of persons suffering from grand mal are subject to statusepilepticus, a sometimes fatal condition in which one attack immediatelyfollows another.

While diet and dehydration have been suggested as practical ways ofraising a patients resistance to epileptic seizures, experience hasshown that both of these methods are usually ineffective.

Various drugs have been employed for controlling epilepsy heretofore.Bromides were the first compounds employed, but these are veryineffective and, furthermore, continued medication results in boils andother skin lesions, somnolence, and mental sluggishness as well as toxicpsychosis. Among other anticonvulsant drugs which have been employedmaybe mentioned: 5-ethyl-5-phenylbarbituric acid (phenobarbital);5,5-diphenylhydantoin (Dilantin); 5-ethyl-3-methyl-5-phenylhydantoin(Mesantoin); 3,5,5-trimethyloxazolidine-2,4-dione (Tridione);3,5-dimethyl-S-ethyloxazolidine-Z,4-dione (Paradione);S-phenyl-S-thienylhydantoiu (Thiantoin); phenylacetyl urea (Phenurone)and 5-ethyl-3-methyl-5- phenylbarbituric acid (Prominal). While many ofthese drugs are often effective in controlling epileptic seizures, theiruse is subject to the following limitations and objections: Most areeifective against only one form of epilepsy, and, moreover, whilecontrolling this form of seizure, they may aggravate another formpresent in the patient and cause it to be more frequent and more severe.For example, patients suifering from both petit and grand mal epilepsyvery often become worse with respect to petit mal when treated forcontrol of grand mal With one or more of the above agents. Many of thesecompounds are relatively ineffective unless they are employed incombination with other anticonvulsant drugs. The most seriousdisadvantage of the antiepileptic drugs employed heretofore is thattheir use gives rise to severe side reactions which are verydisagreeable and discontinuation of the medication.

It has been generally believed that compounds to be of maximumeffectiveness in controlling epilepsy must contain the following groupas part of their structure:

where R represents lower alkyl radicals, phenyl radicals or hydrogen(Toman, I. E. P. and Goodman, L. 8.; Physiological Reviews, 28, 446(1948)). The hydantoins, oxazolidinediones, barbiturates and ureidesmentioned previously contain this grouping as part of their structure.

In accordance with the present invention, it has been found thattherapeutic compositions containing atrolactamide (the amide ofalpha-methyl-mandelic acid) possess valuable and unobvious properties incontrolling epileptic seizures of the grand mal, psychomotor, Jacksonianor petit mal variant types without accentuating any one type of epilepsywhen, as often happens, it occurs with others; Moreover, it has beenfound that these novel compositions produce few side reactions.

Atrolactamide has the following structural formulate Thus, it is readilyapparent that atrolactamide does not possess the essential features ofchemical structure common to the useful anticonvulsants knownheretofore, and therefore it represents a significant departure from thepreviously well-trod paths of research in this field, even throughatrolactamide is a known compound (Staudinger and Ruzicka; Annalen 380,291 (1911)). However, insofar as is known, the physiological propertiesof this compound have never before been investigated or utilized, norhas a therapeutic composition including the compound ever been made orsuggested.

Atrolactamide occurs as a colorless, odorless, crystalline substance,which has a melting point of l00101 C. A freshly prepared aqueoussolution (5%) has a pH of about 6.7. Atrolactamide is soluble in waterto the extent of about 6% at 25 C. Under ordinary conditions of handlingand storage, it is a stable compound. An aqueous solution can besterilized without decomposition by subjecting it to 15 lbs. steampressure for fifteen minutes.

According to the Present invention, therapeutically useful compositionsare provided in dosage form comprising atrolactamide and apharmaceutical carrier which may be either liquid or solid material. Forexample, these compositions include tablets of atrolactamide and acarrier (such as fillers, binders and lubricants) or hard gelatincapsules filled with atrolactamide, or other dosage forms particularlyuseful for oral ingestion. Examples of solid pharmaceutical carriersinclude starch, gelatin, lactose, talc, stearic acid, magnesium stearateor the like. Any of the conventional tableting materials used inpharmaceutical practice may be employed as carrier herein where suchmaterials are compatible with atrolactamide.

'These atrolactamide compositions may also be in the form of sterileparenteral solutions, preferable 6% or more by weight of atrolactamide,dissolved in a sterile parenteral solvent such at water, water andglycerin, water and propylene glycol, or water and paraldehyde. In stillother embodiments, these novel atrolactamide compositions may beprepared in the form of oral solutions or suspensions. Further, sinceatrolactamide is compatible with other well-known drugs useful intreating epileptic patients, it can be associated with them in thedosage forms mentioned above.

Extensive clinical testing has proved these novel atrolactamidecompositions to be highly effective for controlling grand mal,psychomotor, petit mal variant and Iacksonian epileptic seizures, eitheralone or in association with any other form of epileptic seizure.Atrolactamide has also been found to have a high activity rating whentested in vivo by accepted anti-convulsant screening methods employingmice as subjects. Moreover, it was found to be effective incounteracting the action of a wide variety of convulsant agents Whereaspreviously known anticonvulsants have been more or less specific intheir action. I

As used herein, the word controlling should not be construed as implyinga cure for epilepsy or the elimination of epileptic tendencies; but theterm is used solely to denote substantial reduction in the occurrenceand severity of seizures for as long as the medication is continued butnot after medication is stopped. Since it is the occurrence of seizures,not the tendency towards them, which is harmful to the physical, mental,social and economic welfare of the patient, the substantialy benefitsafforded by the present invention will be readily apparent.

To maintain optimum levels of atrolactamide in the blood stream thedaily dosage is preferably divided into four approximately equal doseswhich can conveniently be taken before each meal and before retiring forthe night. The optimum daily dosage for a particular patient is arrivedat in the following manner: The initial dosage is usually about 3 g. forchildren and 4 g. for adults. The dosage is then increased weekly byincrements of 2 g. until the seizures are controlled, or until a furtherincrease in the dosage produces no further decrease in the frequency orseverity of the seizures, or until the maximal dosage is reached. Whilegreater dosages have apparently been well tolerated for brief periods, amaximum daily dosage of about 12 g. is usually preferred. If sidereactions occur, the dosage is reduced or the drug is discontinned untilthe symptoms disappear. Treatment can then usually be resumed, at alower dosage if necessary. If the patient is receiving other medication,this is continued at least until maximal control has been established.These other drugs can then usually be withdrawn more or less rapidlydepending upon their nature and the condition of the patient. Where morethan one form of epilepsy is present, it is sometimes advantageous tocontinue with at least part of the prior medication.

Animals have been found to tolerate atrolactamide in quantities muchgreater than those required for control/ of convulsions. The LD50 (astandard statistical value; which corresponds to the single dose whichis lethal to 50% of the test animals) is 1859 mg. per kg. orally and1417 mg. per kg. intraperitioneally in white mice. The oral LDo (astandard statistical value which roughly corresponds to the maximum,sublethal single dose for of the test animals, and which together withthe LDso is a significant measure of the safety of the drug) is 1500 mg.per kg. of body weight in mice. Atrolactamide when given intravenouslyto a dog at a dosage of 100 mg. per kg. produced definite leg relaxationwithin forty minutes, while a dosage of 500 mg. per kg. produced markeddepression and ataxia within twenty minutes. The effects lasted fortwenty-four hours, but the dog recovered completely. In chronic toxicitystudies, autopsies on mice, sacrificed after receiving approximately1000 mg. per kg. per day each for eighteen days, revealed no grosstissue pathology.

The following examples illustrate the invention:

Example 1 nesium stearate (5 mg.) were combined and tableted inAtrolactamide (500 mg.), gelatin (5 mg.) and mag-' a standard tabletingmachine to form pharmaceutical tablets.

Example 2 A capsule was prepared by filling a No. 0 hard gelatin capsuleweighing 50 mg. with 500 mg. of powdered atrolactamide.

Example 4 A sterile parenteral composition was prepared by dissolvingatrolactamide (3 g.) in a solution consisting of pyrogen-free water (27ml.) and paraldehyde (3 ml.), and subjecting the solution to 15 lb.steam pressure for 15 minutes.

Example 5 A sterile parenteral composition was prepared by dissolvingatrolactamide (3 g.) in a solution consisting of pyrogen-free water (27ml.) and propylene glycol (3 ml.), and subjecting the solution to 15 lb.steam pressure for 15 minutes.

Example 6 The anticonvulsant efficacy of atrolactamide was tested by thesupramaximal electroshock method. White mice, Harlan strain, weighingfrom 17-21 g. were employed as the subjects of the test. None of theanimals had been used previously for any experiments. All animals hadfre access to food and water for at least three days. One hour prior todosing, the animals were taken oif food and water and weighed. Each testgroup contained the same number of animals of approximately equalweight, as did each control group. In every experiment, an aqueoussolution of approximately 1% atrolactamide, with the pH adjusted toneutrality, was employed. All dosage was on a weight basis and dosingwas done orally, unless otherwise noted. The minimal atax-ic dose, i.e., that dose which just produced signs of drug action, was chosen asthe test dose to the used in the experiments. For atrolactamide this wasfound to be 0.4 g. per kg. of body weight.

The apparatus, described by Lanphier, The Evaluation of AntiepilepticDrugs by Laboratory Methods, Thesis (M. S.), University of Illinois,1949, which utilizes a sine wave stimulator delivering a 0.3 secondstimulus through eye electrodes, was used. This instrument will supplystimuli of varying currents. The response of a ormal mouse to asupramaximal stimulus is a seizure pattern that begins with a briefclonus followed by tonic fiexion of all limbs, and then by a longertonic extension (if the limbs and terminates with a few clonic jerks.About 5% of the mice are anoxic at the end of the tonic phase and dieunless given artificial respiration Surviving mice show a typicalpost-seizure depression. Effective compounds abolish these responses inthe reverse order. In general, there is a clinical-laboratorycorrelation between chemicals effective against this supramaximalelectroshock in animals and those useful in the treatment of grand malepilepsy in humans.

It was determined that 7.5 ma. is the threshold current for the mice,and that if 0.25 g. per kg. of body weight of atrolactamide isadministered it will raise the threshold current to 15 ma.

It was also determinedthat the test dose of 0.4 g. of atrolactamide perkg. of body weight gave complete protection at a 90 ma. current stimulusand that not one mortality occurred among the six mice in the testgroup.

tested by the Metrazol method utilizing test subjects,

dosages,- etc., as described in the first paragraph of Exa; ample 6.

In accordance with the timed intravenous infusion method of Orloif,Williams and Pfeilfer, Proc. Soc. Exper. Biol. and Med., 70, 254-257,1949, a 0.5% solution of Metrazol was injected in the mouses tail veinat the rate of 0.05 ml. every seconds. The apparatus employed consistedof a cone-shaped mouse holder made of Plexiglas. The reaction of themouse to the timed Metrazol infusion follows a definite pattern. Theseizure pattern begins with a sharp single twitch followed byintermittent clonic movements which lead to a persistent clonicconvulsion. This persistent convulsion often begins by the mouse pullingits head down under his body. That initiates a tonic flexor componentand the seizure generally terminates in a fatal tonic extensorcomponent. In general, the drugs which are clinically useful in petitmal are also active in elevating the thresholds of the Metrazol tests.

In the group of ten untreated control mice, an average of 0.1401021 ml.of an 0.5% Metrazol solution was required to produce the first twitch,while an average of 0.4051069 of the solution was required to produce apersistent clonus. All the untreated animals suffered immediate deaths.At the test dose of 0.4 mg. atrolactamide per' kg. the thresholds of theMetrazol test for the treated group of ten animals was found to beelevated. In the case of the first twitch, a ratio of 1.21 was observedwhilein the case of the persistent clonus a ratioof 1.25 was observed.No cases of tonic extension Example 8 The anticonvulsant efficacy ofatrolactamide was tested by the strychnine method utilizing testsubjects, dosages,

. etc., as described in the first paragraph of Example 6.

The timed intravenous infusion method of Orloif, Williams and Pfeifier,supra, was used. The technique em ployed is similar to that of theMetrazol test of Example 7 except that 0.01% aqueous solution ofstrychnine is employed. The end point is the tonic extension of the hindlegs of the mouse. The strychnine convulsions are always fatal incontrol animals. Some correlation has been found between strychnineantagonism in mice and activity against psychomotor epilepsy in humansand therefore thhe strychnine test serves as an additional measure ofanticonvulsant activity.

An average of 0200:.026 ml. of 0.01% strychnine solution were requiredto produce a maximal seizure in the eight control animals, and all thecontrol animals suffered immediate deaths. A ratio of 1.25 was observedfor the group of six treated animals and no immediate deaths occurredamong this group. Three of the treated animals suifered delayed deathsand three survived more than 24 hours.

The ratio given above was calculated by comparing the numbers ofmilliliters of the strychnine test solution required to produce aseizure in the treated animals to the number of milliliters required toproduce seizures in a similar group of untreated animals that same day.

Example 9 The anticonvulsant eflicacy of atrolactoamide was tested bythe ammonium ion method utilizing test subjects, dosages, etc., asdescribed in the first paragraph of Example 6.

The timed intravenous technique of Orloif, Williams and Pfeiffer, supra,was employed, but utilizing a 5% ammonium acetate solution. Thissubstance has been demonstrated to produce convulsions with remarkableconsistency. A 5% solution of ammonium acetate having a pH of 7.1 wasused. The response of the mouse to this infusion is very similar to theMetrazol infusion. In both, the tonic extension of the hind legs istaken as the end point. It has been observed that the compoundseffective in modifying the ammonium-induced seizures in mice, are alsoeffective against grand mal seizures in man.

In the group of six control animals, an average of 0366:.141 ml. of a 5%ammonium acetate solution were required to produce this tonic extension(maximal seizure), and all the animals suflfered immediate deaths.Ratios of 1.38 and 1.49 were observed for two groups of six treatedanimals, all of whom suffered immediate deaths.

The ratios given above were calculated by comparing the number ofmilliliters of the ammonium acetate test solution required to produce aseizure in the treated animals to the number of milliliters required toproduce seizures in a similar group of untreated animals that same day.

Example 10 A group of 202 patients affiicted with various forms ofepilepsy were treated. In approximately of these cases, the seizurescould not be satisfactorily controlled using other known anticonvulsantagents. The treatments were over periods of up to two years. Thepatients, most of whom were already receiving medication for 7 epilepsy,were started with a daily dose of 4 g. of atrolactamide, theatrolactamide treatment supplementing other epilepsy drug therapy. Thedaily dosage was gradually increased to an average of 8 g. per day,supplementary As various changes could be made in the above methods andproducts Without departing from the scope of the invention, it isintended that all matter contained in the above description shall beinterpreted as illustrative and medication being discontinued in manyinstances. The 5 not in a li i ng n results are summarized in thefollowing table: I an i TABLE 1 Total Seizures Seizures 1 Seizures Unim-Improved, Diagnosis No. of 50% Con- 75% Con- 100% Conproved percentCases trolled trolled trolled 31 7 13 8 3 90. 3 10 0 2 1 7 30.0 44 13 196 6 86. 4 24 7 8 1 2 8 66. 6 Grand Mal and Psychomotor 77 2 6 3 16 79. 2.Tacksonian 5 0 3 l 1 80.0 .Tacksonian-Gr. Mal-Psychomotor. 4 3 1 0 0100.0 J acksonian and Psychomoton 3 0 3 0 0 100. 0 Jacksonian and GrandMal" l 1 0 0 0 100. 0 Petit Mal and Psychomotor. 2 2 0 0 0 100. 0 GrandMal-Petit Mal-Psychomotor 1 0 1 0 0 100. 0 Totals 202 53 85 23 41 80 0 1Included in this group are many who have gone 3-4 months seizure freeand subsequently have had a few seizuresperhaps due to failure to takemedication.

2 One patient admitted not taking atrolactarnide regularly. 3 Twopatients admitted not taking atrolactamide regularly.

4 Percentage of patients in whom seizures were at least 50% controlled.

It will be noted that out of a total of 202 patients suffering from manyforms of epilepsy 161 patients (80%) experienced 50% or better controlof seizures.

Compositions of the present invention in the form of sterile parenteralsolutions of atrolactamide, e. g., 5 %6% of atr-olactamide in water areparticularly effective in treating patients in status epilepticus. Anillustrative intravenous dosage would be 50 ml. of a sterile parenteralsolution containing 5%6% of atrolactamide.

Patients having both grand mal and petit mal are regarded as beingparticularly difiicult to treat, because in addition to petit malactivity in the electroencephalogram, most cases have petit mal variantactivity. In the above cases where petit mal seizures were notefiectively controlled, they were not aggravated as when most hithertoknown anti-grand mal drugs were employed.

From the above, it will be seen that atrolactamide is highly etfectivein controlling epileptic seizures. Moreover, atrolactamide has notcaused undesirable changes in behavior or personality. Side reactionswere infrequent even though the daily dosage ranged up to 12 g., theusual daily dose being 4-8 g. per patient. Although in many instancesseizures are controllable by other medications, patients are irritable,pugnacious or even violent, whereas when placed on atrolactamidetherapy, these patients become cooperative, calm, and invariably expressa feeling of well-being.

The instant compositions for combating epileptic seizures may be used ina variety of forms, and the percentage of active ingredients in thesecompositions may be varied. However, it is necessary that the activeingredient be present in such amount as will give a suitable dosage.While up to 16 grams per day have been administered, in general it ispreferred that the daily dose for effective control of seizures in anadult patient, be between 312 grams per day. Based on the above-notedclinical studies the average daily dose is about 8 grams. It ispreferred that dosage units containing at least approximately 0.5 gramof atrolactamide be used.

While, in general, it is preferred that the solid dosage forms such astablets or capsules shall contain as much atrol'actamide as is feasiblewithout rendering these tablets or capsules unduly bulky, smallertablets or capsules with a smaller amount of atrolactamide may beemployed if desired. However, in that event a correspondingly largernumber of tablets or capsules must be administered to provide the dailydosage specified above.

In View of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

1. A composition in dosage form for controlling epileptic seizures,comprising not less than approximately 5% by weight of atrolactamide andnot less than approximately 2% by weight of a pharmaceutical carrier.

2. A composition in tablet form for controlling e ileptic seizures,comprising not less than approximatel 5% by weight of atrolactamide andnot less than ap roximately 2% by weight of a pharmaceutical carrier.

3. A composition in tablet form for controlling epileptic seizures,comprising approximately 98% by weight of atrolactamide andapproximately 2% by weight of a pharmaceutical carrier, said carriercomprising magnesium stearate and gelatin.

4. A composition in capsule form for controlling epileptic seizures,comprising not less than approximately 5% by weight of atrolactamide andnot less than approximately 2% by weight of a pharmaceutical carrier.

5. A composition in capsule form for controlling epilep" tic seizures,comprising approximately by weight of atrolactamide and approximately10% by weight of gelatin.

6. A composition in sterile parenteral solution form for controllingepileptic seizures, comprising not less than approximately 5% by weightof atrolactamide and pyrogen-free water.

7. A composition in sterile parenteral solution form for controllingepileptic seizures, comprising not less than approximately 5% by weightof atrolactamide diss lved in a parenteral solvent comprising water anda subs ance selected from "the group consisting of paraldehyde,glycerin, and propylene glycol.

8. A process for controlling epileptic seizures which comprisesadministering to a human being a daily dosage of not more thanapproximately 16 grams of atro lactamide.

9. A process for controlling epileptic seizures which comprisesadministering parenterally to a human being a dosage of approximately2-5 grams of atrolactamide.

10. A process for controlling epileptic seizures which comprisesadministering to a human being a daily dosage of approximately 3-12grams of atrolactamide.

References Cited in the file of this patent

1. A COMPOSITION IN DOSAGE FORM FOR CONTROLLING EPILEPTIC SEIZURES,COMPRISING NOT LESS THAN APPROXIMATELY 5% BY WEIGHT OF ATROLACTAMIDE ANDNOT LESS THAN APPROXIMATELY 2% BY WEIGHT OF A PHARMACEUTICAL CARRIER.